Synthesis and characterization of new disulfoxides, and their Ru complexes

a,b

a

a,

Elizabeth L.S. Cheu, Donald T. T. Yapp, Lynsey Huxham, Brian O Patrick, Brian R. James *

a

Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada

b

Advanced Therapeutics, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada

II

III

Keywords: Disulfoxides; Ru ; Ru ; Ru Ru ;Ru ; complexes; X-ray structures

2

ABSTRACT

Reported are the syntheses of ten, new disulfoxides, and four known ones, of the type R-S(O)-CH ) -

2

n

(O)S-R (n = 2 or 3, R = alkyl) that were formed by oxidizing the corresponding dithioethers,

RS(CH ) SR, using acid solutions of DMSO or H O as oxidants. The disulfoxides were then reacted

2

n

2

with either commercial RuCl

٠

H O, K (RuCl ), or the so-called Ru ‘Blue’ or ‘Red’ solutions, in

3

2

3

6

aqueous or alcohol (MeOH, EtOH) solution from which various S-bonded sulfinyl complexes of the

II

type

cis

or

trans-Ru Cl (disulfoxide)

[Ru Cl (disulfoxide)(H O)] (μ-Cl) ,

and

2

2,

2

[

Ru₂^I^I^/^I^I^ICl(disulfoxide)] (μ-Cl) were isolated; all three types are well characterized, including X-ray

2

3

III

data. One Ru complex, formulated RuCl (BPhSE)] (BPhSE) with the bridging disulfoxide 1,2-

3

2

bis(phenylsulfinyl)ethane, is also synthesized, but less well characterized.

1

. Introduction

We reported recently on the synthesis of nine new dithioethers of the type RS(CH ) SR, where n = 2

2

n

or 3, and R is an alkyl chain [1]; synthesis and data of two known analogues where n = 2 or 3 and R =

phenyl, were also presented. The aim was to oxidize these to the corresponding disulfoxide species

RS(O)CH ) (O)SR, because of the potential biological properties of their Ru complexes; e.g., anti-

2

x

cancer, radiosensitizer, and hypoxic activities have been reported for some Ru compounds containing

sulfoxide or disulfoxide ligands [2,3]. This current paper reports on the syntheses of the disulfoxides,

and their reactions with various Ru-precursors to form S-bonded sulfinyl complexes of the type cis or

II

II/III

trans-Ru Cl (disulfoxide) [Ru Cl (disulfoxide)(H O)] (μ-Cl) , and [Ru

Cl (disulfoxide)] (μ-Cl) ;

2 3

2

2,

2

all types are well characterized, including X-ray data. Some in vitro studies on such complexes, such as

cell accumulation and toxicity, and binding to DNA [4], will be reported later. This paper is the second

of three: the first reported on the dithioethers and some of their Ru complexes [1], and the third will

describe later the in vitro studies.

1

*

Corresponding author. E-mail address: brj@chem.ubc.ca (B.R. James).

2

. Experimental section

2

.1. General

The dithioethers, required as precursors for oxidation to the corresponding disulfoxide, were

prepared and characterized as described [1,3,4]. Table 1 shows the names and abbreviations used for

thedisulfoxides; the conversion of the dithioether to the disulfoxide in each case involves a change in the

T of the abbreviation (meaning ‘thia’) to S (meaning sulfinyl), e.g. in Section 2.2.1, BESP is

synthesizedfrom BETP. The known 3,6-dithiaoctane, viz bis(ethylthio)ethane (BETE), 4,7-dithiadecane,

viz bis(propylthio)ethane (BPTE), and 1,2 bis(phenylthiol)ethane (BPhTE), were purchased from K & K

Laboratories, and were similarly oxidized to the corresponding known disulfoxides, BESE, BPSE,

andBPhSE [3,5]. 3,5 Dithiaseptane, viz bis(ethylthio)methane (BETM), was synthesized as reported [6].

Table 1. Names and abbreviations used for the synthesized R-S(O)-CH ) -(O)S-R

2

n

disulfoxides; the first 5 (in italics) are known compounds (see Section 3.1, Table 2).

n

R

methyl

ethyl

propyl

phenyl

methyl

Name

Abbreviation

BMSE

2

3

1,2-bis(methylsulfinyl)ethane

1,2-bis(ethylsulfinyl)ethane

1,2-bis(propylsulfinyl)ethane

1,2-bis(phenylsulfinyl)ethane

1,3-bis(methylsulfino)propane

i

BESE

BPSE

BPhSE

BMSP

2

3

n-butyl

n-hexyl

cyclohexyl

n-pentyl

ethyl

1,2-bis(butylsulfinly)ethane

1,2-bis(hexylsulfinyl)ethane

1,2-bis(cyclohexylsulfinyl)ethane

1,2-bis(pentylsulfinyl)ethane

1,3-bis(ethylsulfinyl)propane

1,3-bis(propylsulfinyl)propane

1,3-bis(i-propylsulfinyl)propane

1,3-bis(butylsulfinyl)propane

1,3-bis(pentylsulfinyl)propane

1,3-bis(phenylsulfinyl)propane

BBSE

BHSE

BCySE

BPeSE

BESP

BPSP

n-propyl

i-propyl

n-butyl

n-pentyl

phenyl

i

B PSP

BBSP

BPeSP

BPhSP

2

in Section 2.2.1, BESP is synthesized from BETP. The known 3,6-dithiaoctane, viz bis(ethylthio)ethane

BETE), 4,7-dithiadecane, viz bis(propylthio)ethane (BPTE), and 1,2 bis(phenylthiol)ethane (BPhTE),

(

were purchased from K & K Laboratories, and were similarly oxidized to the corresponding known

disulfoxides, BESE, BPSE, and BPhSE [3,5]. 3,5 Dithiaseptane, viz bis(ethylthio)methane (BETM), was

synthesized as reported [6].

Common chemicals and solvents used were at least of reagent grade, and were purchased from Fisher

Scientific, and used as provided; deuterated solvents CDCl , D O were purchased from MSD Isotopes.

3

2

RuCl ·3H O was donated by Colonial Metals Inc.; K [RuCl ] and cis-RuCl (DMSO) were made as

3

2

3

6

2

4

reported [7]; the so-called “Ru-blue solution” [8] was generated by refluxing a MeOH solution of

RuCl ·3H O under H for ~4 h; and the so-called “Ru-red solution” [9] was made by heating, under

3

2

reflux in air for ~2 h, an EtOH solution of RuCl ·3H O in the presence of HCl acid.

3

2

Syntheses of the disulfoxides are described in Section 2.2. All samples (products and solvents) were

stored in air, and all syntheses and measurements were carried out in air, unless noted otherwise.

II

III

Syntheses of Ru and dinuclear Ru complexes, a dinuclear Ru /Ru complex, and a dinuclear Ru

2

complex, are described in Sections 2.3, 2.4, 2.5 and 2.6, respectively. The complex, trans-

RuCl (BMSE) was made via the Ru-blue solution as reported [3].

2

Elemental analyses (EA) were performed in the UBC chemistry department on a Carlo Erba 1106

instrument, with data having an accuracy of ±0.3%. Melting points (M.p., given in ºC) were obtained

using a Fisher-Johns apparatus and are uncorrected.

Unless stated otherwise, NMR spectra were obtained in CDCl solutions of the compounds using a

3

Bruker AC-200E (200 MHz) instrument. The proton shifts, indicated by d = doublet, t = triplet; quin =

quintet; m = multiplet, br = broad, are given with reference to the residual CHCl solvent peak ( 7.24)

3

-1

as the internal standard, relative to TMS. IR spectra (reported in cm ) were obtained using an ATI

Mattson Genesis Series FTIR instrument, solid pellet samples being prepared by mixing the compound

with KBr. UV-visible data were measured on a Hewlett-Packard 8452A diode array spectrophotometer,

_m_a_xbeing given in nm, followed by an extinction coefficient given as log . Mass spectra were

measured using +LSIMS on a KRATOS Concept IIHQ.

III

Determination of the _e_f_fand number of unpaired electrons for paramagnetic Ru complexes was

◦

performed at room temperature (r.t. ~20 C) using a Johnson-Matthey Mk1 Magnetic Susceptibility

-1

2

-1

Balance. Molar conductance measurements, reported as Ʌ (Ω cm mol ), were carried out at r.t. at

M

3

-3

~

10 M concentrations using a Thomas Serfass conductivity bridge, and a cell from Yellow Springs

-1

Instrument Company, the cell constant being determined as 1.016 cm . Thermal gravimetric data were

collected using a TGA 51 Analyzer fitted with a quartz furnace tube with a temperature range from

ambient to 1200 ºC. Column chromatography was performed on Merck silica TLC Al sheets (silica gel

6

0F254). Photochemical experiments were carried out at r.t. using an Ace-Hanovia 450Watt high

pressure Hg vapour lamp (cat. #7825-34, Ace Glass Inc.).

2

.2. Synthesis of Disulfoxides

.2.1. 1,3-Bis(ethylsulfinyl)propane (BESP)

A stirred solution of 3,7-dithianonane (BETP), 10 mL, 60 mmol), DMSO (9.5 mL, 120 mmol) and

conc. HCl (200 L) was heated at 85 ºC for 8 h. A cooling of the solution to 0 ºC precipitated a white,

crystalline product that was collected, and washed with acetone to remove excess DMSO and dimethyl

sulphide. The filtrate was re-heated for a further 4 h, and gave more product. The disulfoxide was

recrystallized from EtOH (50 mL) three times, and then dried under vacuum Yield 7.8 g (65 %). Anal.

1

Calc. (found) for C H O S : C, 42.83 (43.1); H, 8.21 (8.2) %. H-NMR:  2.90 (m, 8H, CH S(O)CH ),

7

16

2

.45 (m, 2H, CH CH CH ), 1.35 (t, 6H, CH ). IR  : 1016, 1047. M.p.:127-130.

2

3

SO

2

.2.2. 1,3-Bis(propylsulfinyl)propane (BPSP)

BPSP was prepared according to the procedure given in Section 2.2.1, but using 4,8-dithiaunadecane

(BPTP, 10 mL, 52 mmol), DMSO (8 mL, 100 mmol) and conc. HCl (200 L). Yield 8.9 g (77 %).

1

Anal. Calc. (found) for C H O S : C, 48.18 (48.1); H, 8.98 (9.1) %. H-NMR:  3.00 (m, 4H,

9

20

2 2

CH CH CH ), 2.90 (m, 4H, CH S(O)), 2.20 (m, 2H, CH CH CH ), 1.80 (m, 4H, CH CH CH ), 1.07 (t,

2

3

6

H, CH ). IR  : 1021, 1075. M.p.: 140-143.

3

SO

i

2

.2.3. 1,3-Bis(i-propylsulfinyl)propane (B PSP)

i

B PSP was prepared basically via the Section 0 procedure, but using 2,8-dimethyl-3,7-dithianonane

i

(

B PTP, 10 mL, 52 mmol), DMSO (8 mL, 100 mmol) and conc. HCl (200 L). The white disulfoxide

precipitated when the reaction mixture was cooled to 0ºC, after the sides of the flask were scratched and

Et O (30 mL) was added. Yield 2.3 g (20 %). Anal. Calc. (found) for C H O S : C, 48.18 (48.3); H,

2

9

20

2 2

4

1

8

.98 (9.1) %. H-NMR:  2.75 (m, 6H, CHS(O)CH CH CH S(O)CH), 2.35 (m, 2H, CH CH CH ), 1.35

2

(

d, 12H, (CH ) ). IR  : 1016.

3

2

SO

2

.2.4. 1,3-Bis(butylsulfinyl)propane (BBSP)

BBSP was prepared as above, but using 5,9-dithiatridecane (BBTP, 10 mL, 45 mmol), DMSO (7 mL,

9

0 mmol) and conc. HCl (200 L). Yield 9.9 g (87 %). Anal. Calc. (found) for C H O S : C, 52.34

1

24

2 2

1

(

52.4); H, 9.58 (9.6) %. H-NMR:  2.80 (m, 8H, CH S(O)CH ), 2.40 (m, 2H, CH CH CH ), 1.75 (quin,

2

4

H, CH CH CH ), 1.50 (brs, 4H, CH CH ), 0.95 (t, 6H, CH ). IR  : 1021. M.p: 146-148.

3

2

3

2

3

SO

2

.2.5. 1,3-Bis(pentylsulfinyl)propane (BPeSP)

BPeSP was prepared as in Section 0, but using 6,10-dithiapentadecane (BPeTP, 10 mL, 40 mmol),

DMSO (6 mL, 80 mmol) and conc. HCl (200 L). Yield 3.3 g (29 %). Anal. Calc. (found) for

1

C H O S : C, 55.67 (55.5); H, 10.06 (10.1) %. H-NMR:  2.70 (m, 8H, CH S(O)CH ), 2.25 (m, 2H,

1

3

28

2

CH CH CH ), 1.68 (quin, 4H, CH CH CH CH ), 1.28 (m, 8H, CH CH CH ), 0.85 (t, 6H, CH ). IR  :

2

3

2

3

2

3

SO

1

026. M.p: 125-129.

2

.2.6. 1,3-Bis(phenylsulfinyl)propane (BPhSP)

,3-Bis(phenylthio)propane (BPhTP, 10 g, 38 mmol) was added to 200 mL of glacial acetic acid, and

the solution was cooled to 0 ºC, when 9 mL of 30 % H O (76 mmol) was then added, and the resulting

1

2

solution stirred for 24 h at r.t. prior to extraction with CHCl (3 x 50 mL portions). The CHCl was then

3

neutralized with a saturated NaHCO solution, and then the CHCl layer was washed with H O and

3

2

dried over MgSO . The MgSO was removed and the CHCl was removed by rotary evaporation to leave

4

3

a white crude product; this was recrystallized with a CH Cl (7 mL) and Et O (50 mL) mixture. Yield

2

1

2

1

.1 g (19 %). Anal. Calc. (found) for C H O S : C, 61.61 (61.4); H, 5.51 (5.4) %. H-NMR:  7.50 (m,

1

5

16

2 2

0H, C H ), 2.90 (m, 2H, CH CH CH ), 2.15 (m, 4H, CH CH CH ). IR  : 1021, 1040, 1084. M.p:

6

5

2

SO

37-140.

2

.2.7. 1,2-Bis(butylsulfinyl)ethane (BBSE)

BBSE was prepared as in Section 2.2.1, but using 5,8-dithiadodecane (BBTE, 10 mL, 48 mmol) in

DMSO (8 mL, 97 mmol) and conc. HCl (200 L). Yield 2.3 g (20 %). Anal. Calc. (found) for

5

1

C H O S : C, 50.37 (50.3); H, 9.30 (9,4) %. H-NMR:  3.20, 3.00 (m, 2H each, S(O)CH CH S(O)),

1

0

22

2

1

.75 (m, 4H, CH S(O)), 1.72 (m, 4H, CH CH CH ), 1.45 (m, 4H, CH CH ), 0.95 (t, 6H, CH ). IR  :

2

3

2

3

2

3

SO

014. M.p: 172-173.

2

.2.8. 1,2-Bis(pentylsulfinyl)ethane (BPeSE)

BPeSE was prepared as in Section 0, but using 6,9-dithiatetradecane (BPeTE, 10 mL, 40 mmol) in

DMSO (7 mL, 80 mmol) and conc. HCl (200 L). Yield 3.9 g (34 %). Anal. Calc. (found) for

1

C H O S : C, 54.09 (54.1); H, 9.83 (10.1) %. H-NMR:  3.20, 3.10 (m, 2H each, S(O)CH CH S(O)),

1

2

26

2

.80 (m, 4H, CH S(O)), 1.80 (m, 4H, CH CH CH CH ), 1.40 (m, 8H, CH CH CH ), 0.93 (t, 6H, CH ).

2 3 2 2 2 3 2 2 3

IR  : 1014, 1073, 1100. M.p: 134-135.

SO

2

.2.9. 1,2-Bis(hexylsulfinyl)ethane (BHSE)

BHSE was prepared as in Section 0, but using 7,10-dithiahexadecane (BHTE, 10 mL, 38 mmol) in

DMSO (6 mL, 76 mmol) and conc. HCl (200 L). Yield 6.2 g (55 %). Anal. Calc. (found) for

C H O S : C, 57.09 (57.0); H, 10.27 (10.2) %. ¹H-NMR:  3.20, 3.10 (m, 2H each,

1

4

30

2 2

S(O)CH CH S(O)), 2.80 (m, 4H, CH S(O)), 1.80 (m, 8H, CH CH CH CH CH ), 1.40 (m, 8H,

2

3

2

CH CH CH ), 0.93 (t, 6H, CH ). IR  : 1016, 1114. M.p: 176.5-177.5.

3

2

3

SO

2

.2.10. 1,2-Bis(cyclohexylsulfinyl)ethane (BCySE)

BCySE was prepared as in Section 0, but using 1,2-bis(cyclohexylthio)ethane (BCyTE, 10 mL, 40

mmol) in DMSO (6 mL, 77 mmol) and conc. HCl (200 L). Yield 9.1 g (80 %). Anal. Calc. (found) for

1

C H O S : C, 57.89 (58.1); H, 9.02 (9.1) %. H-NMR (CDCl , 400 MHz):  3.60 (m, 4H, CH CH ),

1

4

26

2

3

2

.56, 2.15 (m, 2H each, H ), 1.69 (m, 2H, H ), 1.35 (m, 12H, H ); H atoms numbered as for BCyTE

2 1 3,4

[

1]. IR  : 1018. M. p: 172-174.

SO

2

.3. Synthesis of mononuclear Ru(II) disulfoxide complexes

.3.1 Trans-RuCl (BMSE) (1)

2

Complex 1 was made in 80% yield by addition of BMSE to the Ru-blue solution, as reported [3].

2

.3.2. Cis-RuCl (BESE) (2)

2

6

A solution of BESE (210 mg, 1.2 mmol) in MeOH (5 mL) was added to a solution of K [RuCl ]

3

6

(

250 mg, 0.6 mmol) in H O (15 mL), and the mixture then heated to 50 ºC for 5 h, during which the

2

light brown solution became yellow and a yellow precipitate formed. Yield 112 mg (36 %). Anal. Calc.

1

(

found) for C H Cl O RuS : C, 26.86 (26.7); H, 5.26 (5.2) %. H-NMR (D O, 200 MHz)  3.95-2.95

1

2

28

2

4

2

(

m, 16H, CH S(O)CH ), 1.45, 1.30 (t, 6H each, CH ). IR  : 1092, 1122. The spectroscopic data agree

2

3

SO

well with those previously reported [3].

2

.3.3. Trans-RuCl (BESE) H O (3)

2

To a solution of [RuCl(BESE)(H O)] (-Cl) (25 mg, 0.035 mmol (see Section 0) in H O (10 mL) was

2

added BESE (12.2 mg, 0.07 mmol), and the resulting yellow solution was refluxed for 4 h before being

reduced in volume; the product formed as a crystalline powder. X-ray quality crystals were formed by

slow evaporation of an aq. solution of the complex. Yield 12 mg (33 %). Anal. Calc. (found) for

1

C H Cl O RuS ·H O: C, 25.98 (26.1); H, 5.4 (5.2) %. H-NMR (D O, 200 MHz):  3.70 (m, 16H,

1

2

28

2

4

2

CH S(O)CH ), 1.45 (m, 12H, CH ). IR  : 1093, 1119. UV-Vis (H O) 374 (2.78), 310 (3.19).

2

3

SO

2

.3.4. Trans-RuCl (BPSE) H O (4)

2

To a solution of cis-RuCl (DMSO) (172 mg, 0.36 mmol) in MeOH (10 mL) was added a solution of

2

4

BPSE (150 mg, 0.70 mmol) in MeOH (5 mL). The resulting yellow solution was refluxed for 3 h when a

yellow precipitate formed. Yield 99 mg (47 %). Anal. Calc. (found) for C H Cl O RuS ·H O: C,

1

6

36

2

4

2

1

3

1.47 (31.6); H, 6.27 (5.9) %. H-NMR:  3.75, 3.35 (m, 8H each, CH S(O)CH ), 2.30, 2.85 (m, 4H

2

each, CH CH ), 1.10 (t, 12H, CH ). IR  : 1094. The spectroscopic data agree well with those reported

3

2

3

SO

[3].

Other methods using RuCl 3H O and K [RuCl ] as precursors for the attempted synthesis of cis-

3

2

3

6

RuCl (BPSE) also led to isolation of trans-RuCl (BPSE) .

2

.3.5. Cis-RuCl (BBSE) (5)

2 2

Conc. HCl (100L) was added to a solution of RuCl ·3H O (100 mg, 0.4 mmol) in EtOH (30 mL),

3

2

and the mixture was refluxed for 5 h; BBSE (182 mg, 0.8 mmol) was then added, and the mixture was

refluxed for a further 6 h. The resulting yellow solution was then reduced in volume until a fine yellow

7

precipitate formed, and this was collected. Yield 52 mg (21 %). Anal. Calc. (found) for

C H Cl O RuS : C, 37.03 (37.0); H, 6.83 (6.8) %. X-ray quality crystals of an EtOH solvate were

2

0

44

2

4

1

formed by slow evaporation of an EtOH/CH Cl solution of the complex. H-NMR:  3.60 (m, 16H,

2

CH S(O)CH ), 1.55 (m, 16H, CH CH CH ), 0.98 (m, 12H, CH ). IR  : 1081, 1126. UV-Vis (CH Cl )

2

3

2

3

SO

2

36 (4.38).

2

.3.6. Cis-RuCl (BPeSE) (6)

2 2

The procedure was as in Section 2.3.5, but using BPeSE (204 mg, 0.8 mmol). The yellow product was

purified by column chromatography using neutral alumina with 5 % EtOH/CH Cl . Crystals, obtained

2

by slow evaporation of an EtOH/CH Cl solution of the complex, were subjected to X-ray analysis, but

2

excessive thermal motion due to the long pentyl groups prevented an accurate structure determination;

however, cis-geometry was established. Yield 24 mg (9 %). Anal. Calc. (found) for C H Cl O RuS :

2

4

52

2

4

1

C, 40.89 (41.0); H, 7.43(7.6) %. H-NMR:  3.70 (m, 16H, CH S(O)CH ), 2.30, 1.85 (m, 4H each,

2

CH CH S(O)), 1.45 (m, 16H, CH CH CH ), 0.90 (m, 12H, CH ). IR  : 1081, 1128. UV-Vis

2

3

2

3

SO

(

CH Cl ) 240 (4.17).

2 2

2

.3.7. Cis-RuCl (BCySE) (7)

2 2

The procedure used was as in Section 2.3.5. but using BCySE (222 mg, 0.8 mmol) The collected,

orange-yellow precipitate was collected. Yield 86 mg (30 %). Anal. Calc. (found) for

C H Cl O RuS : C, 44.67 (44.3); H, 6.96 (7.0) %. Crystals suitable for X-ray analysis were formed by

2

8

52

2

4

1

slow evaporation of the reaction solution. The H-NMR spectrum of the title complex is a complicated

1

3

pattern of overlapping multiplets in the  1.0-4.4 region. Attempts to assign the spectrum using C,

1

HETCOR, ATP and H decoupling experiments were unsuccessful. IR  : 1046, 1100. UV-Vis

SO

(

CH Cl ) 428 (2.81), 338 (3.01).

2 2

2

.3.8. Cis-RuCl (BESP) (8)

2 2

The procedure used was described in Section 2.3.5, but using BESP (150 mg, 0.8 mmol); the

resulting yellow solution was evaporated to near dryness, and the complex was purified by column

chromatography as described in Section 2.3.6. Yield 77 mg (36 %). Anal. Calc. (found) for

C H Cl O RuS : C, 29.78 (29.6); H, 5.71 (5.8) %. Crystals (containing one EtOH and one H O solvate

1

4

32

2

4

2

8

molecules) suitable for X-ray analysis were formed by vapour diffusion of EtOH into a CH Cl solution

2

1

of the complex. H-NMR (CDCl , 200 MHz)  3.45 (m, 16H, CH S(O)CH ), 2.75, 2.10 (m, 2H each,

3

2

CH CH CH ), 1.45 (m, 12H, CH ). IR  : 1042, 1088. UV-Vis (CH Cl ) 348 (2.62), 262 (4.04), 246

2

3

SO

2

(4.01).

2

.4. Synthesis of dinuclear Ru(II) disulfoxide complexes

2

.4.1. [RuCl(BESE)(H O)] (-Cl) (9)

2

The procedure used was as given in Section 2.3.5, but using BESE (70 mg, 0.4 mmol). The yellow

precipitate was collected. Yield 87 mg (60 %). Anal. Calc. (found) for C H Cl O RuS : C, 19.35

6

16

2

3

2

1

(

19.6); H, 4.33 (4.38); S, 17.22 (17.4) %. H-NMR (D O, 200 MHz):  3.60 (m, 16H, CH S(O)CH ),

2

1

.50 (m, 12H, CH ). UV-Vis (H O) 424 (2.63), 326 (3.16), 278 (3.42), 238 (3.47). IR  : 1042, 1071,

3

2

SO

118. Crystals for X-ray analysis were formed by slow evaporation of an aq. solution of the complex,

and were found to contain one H O solvate per molecule. TGA (crystals): Calc. for loss of 3H O, 7.1 %,

2

and plus loss of 2BESE, 51.5 %; found: 6.8 % (from ~20 to ~220C) and 46.0 % (from ~220

to ~370C).  358 (in H O, increasing to this steady value after 20 min).

M

2

.4.2. [RuCl(BPSE)(H O)] (-Cl) (10)

2

The procedure used was as given in Section 2.3.5 but using BPSE (84 mg, 0.4 mmol) to give the

collected, yellow precipitate. Yield 70 mg (46 %). Anal. Calc. (found): for C H Cl O RuS : C, 24.00

8

20

2

3

2

1

(

23.6); H, 5.03 (4.8) %. H-NMR (D O, 400 MHz)  3.70 (m, 16H, CH S(O)CH ), 2.00 (m, 8H,

2

CH CH ), 1.05 (m, 12H, CH ). IR  : 1048, 1083, 1119. UV-Vis (H O): 268 (4.60).  282 (in H O,

2

3

SO

2

M

2

increasing to this steady value after 30 min).

.4.3. [RuCl(BBSE)(H O)] (-Cl) (11)

2

The procedure used was that of Section 2.3.5, but using BBSE (95 mg, 0.4 mmol). The yield of the

yellow precipitate was 100 mg (61 %). Anal. Calc. (found) for C H Cl O RuS : C, 28.04 (28.5); H,

1

0

24

2

3

2

1

5

1

.43 (5.4) %. H-NMR (D O, 400 MHz)  3.65 (m, 16H, CH S(O)CH ), 2.00 (m, 8H, CH CH CH ),

2

3

.49 (m, 8H, CH CH ), 0.95 (m, 12H, CH ). IR  : 1046, 1098, 1116. UV-Vis (H O): 424 (2.92), 268

2

3

SO

2

(

4.39).  497 (in H O, increasing to this steady value after 30 min).

M

2

9

2

.5. Synthesis of a dinuclear Ru(II)/Ru(III) disulfoxide complex

.5.1.[RuCl(BPSP)] (-Cl) (12)

2

3

The procedure used was again that of Section 2.3.5, but with use of BPSP (172 mg, 0.8 mmol). A final

orange solution was evaporated to near dryness, when CH Cl (5 mL) was added, and X-ray quality

2

crystals formed during slow evaporation of the solution. EA was done on a crushed crystal that was

dried in vacuo at 70 ºC overnight. Yield 24 mg (15 %). Anal. Calc. (found) for C H Cl O Ru S : C,

1

8

40

5

4

2 4

1

2

6.11 (26.1); H, 4.87 (5.1) %. H-NMR:  2.18 (broad peak), 1.10 (broad peak). H-NMR (D O, 200

2

MHz)  3.95 (m, 4H, S(O)CH CH CH S(O)), 3.40 (m, 4H, CH S(O)), 2.62 (m, 2H, CH CH CH ), 1.90

2

(

m, 4H, CH CH CH ), 1.10 (m, 6H, CH ). IR  : 1053, 1084. UV-Vis (immediately upon dissolution

2

3

SO

in CH CN): 424 (2.52), 324 (2.94), 286 (3.32). UV-Vis (after 20 min in H O) 450 (3.78), 318 (4.42),

3

2

82 (4.78). No conductivity was observed in CH CN.  2 (CHCl , time independent).  234 (H O,

3

M

3

M

2

increasing to a steady value at 20 min). The colour of the solutions used for UV-Vis and conductivity

did not change over the period of the experiments. The crystal structure revealed the presence of 2 H O

2

and 2.5 CH Cl per molecule. TGA (crystals formulated as2 H O or2 H O2.5 CH Cl , the two crystal

2

formulae being used since the CH Cl solvates are readily lost at ambient conditions). Calc. for loss of

2

H O, 4.2 or 3.3 %, and for loss of 2BPSP, 54.2 %; found: 6.1 % (from ~20 to ~200 C) and 51.9 %

2

(

from ~200 to ~300 C).  = 1.7  0.1 B. M.

eff

2

.6. Synthesis of a dinuclear Ru(III) disulfoxide complex

.6.1. [RuCl (BPhSE)] (BPhSE)x H O : x = 1 (13a), 2 (13b)

3

2

(

a) A solution of RuCl 3H O (100 mg, 0.38 mmol) in MeOH (30 mL) and conc. HCl (100 L) was

3

2

refluxed under 1 atm N for ~2 h when the colour became light orange. BPhSE (222 mg, 0.80 mmol)

2

was then added and the solution refluxed under N for another 5 h, this forming a yellow precipitate.

2

(

b) BPhSE was also refluxed with RuCl 3H O in EtOH according to the procedure reported in Section

3

2

.3.5.

(

c) BPhSE was similarly reacted with the other Ru precursors K [RuCl ], the Ru ‘Blue’ [8] solution, and

3 6

the Ru ‘Red’ solution [9].

All the above procedures generated yellow precipitates that were filtered off, washed twice with

o

1

EtOH, and dried overnight in vacuo at 70 C. H NMR (CD Cl , 300 MHz) (paramagnetic):  3.9 (bs,

2

1

0

CH ), 7.4 (bm, Ph groups). Anal. Calc. for C H Cl O S Ru H O: C, 39.78; H, 3.50. Anal. Found (for

2

42 42

6

2

syntheses using RuCl 3H O and K [RuCl ]) C, 39.74 - 39.81; H, 3.64 - 3.81%. Anal. Calc. for

3

2

3

6

C H Cl O S Ru 2H O: C, 39.22; H, 3.61. Anal. Found (for syntheses using Ru ‘Blue’ and ‘Red’

4

2

42

6

2

solutions) C, 39.09 - 39.22; H, 3.49 - 3.56 %. IR  : 1070, 1082, 1105, 1116. Mass spectrum [LSIMS,

so

+

m/z, matrix: thioglycerol]: 1142 [M - 3Cl], 972 [M - BPhSE].  (CH Cl ): 0.6.

M

2

.7. X-ray crystallography

The data for the six structures were collected on a Rigaku AFC7/ADSC CCD diffractometer with

graphite monochromated Mo-K radiation. All crystals were mounted on glass fibers with oil, and data

were collected at -93 °C. Data for complex 3 were collected to a maximum 2θ of 64.3°, whereas data

for 5, 8, and 12 were all collected to a maximum of 60.1°; for 7 and 9, the maximum was 59.9 and 61.1°,

respectively. The structures were solved using Intrinsic Phasing [10] and refined using Shelxl-2018 [11].

Complex 12 crystallizes with two crystallographically independent molecules, with five CH Cl and

2

four H O molecules in the asymmetric unit of which two CH Cl and one H O molecule are disordered

2

and thus modeled in two orientations; 8 crystallizes with one EtOH and one H O molecule in the

2

asymmetric unit; the EtOH is disordered and was modeled in two orientations; 5 has one disordered

butyl group that was modeled in two orientations, in addition to one disordered EtOH solvent; 7

crystallizes with two disordered cyclohexyl groups, each modeled in two orientations. Additionally,

there was residual electron density from solvent molecules that could not be modeled, and as a result the

PLATON/SQUEEZE program was used to generate a solvent-free data set. Complex 9 crystallizes with

two half-molecules and one H O molecule in the asymmetric unit. All none H-atoms were refined

2

anisotropically, and the H-atom positions were calculated geometrically and refined using a riding

model.

3

. Results and discussion

3

.1. The disulfoxides

Ten new disulfoxides (Table 1) were synthesized by oxidation of the corresponding dithioethers

using literature methods. The dialkylsulfoxides were synthesized by an acid catalyzed, DMSO oxidation

13], whereas the diarylsulfoxides were synthesized by H O oxidation [14]. The disulfoxides are

[

2

1

characterized by EA, IR and H NMR spectroscopies, and melting points (Section 2.2, and Table 2).

1

Other methods for oxidizing sulfides to sulfoxides are known [15].

The new disulfoxides were synthesized as mixtures of diastereomers (the RR/SS pair, and the meso

RS/SR) but, as reported, use of several recrystallizations can yield one diastereomer [5,16], and

separation of the BPhSE enantiomers has been achieved by column chromatography on lactose [17]. A

report has stated that the sole product obtained from the DMSO oxidation is the higher melting isomer,

which has been identified as the racemic mixture of the RR and SS forms [18]. However, X-ray analyses

-1

Table 2. Melting points and  (cm ) for disulfoxides.

SO

-

1

Compound M. p. (ºC)

a

 (cm ) [ref]

Ref.

SO

b

c

e

BMSE(RS) 158-162 and 165-166 ; 163-164; 169-170; 36;14;13;16 1018 [3,13]

d

174-175

b

f

c

d

1018 [3,13]^e

18;13;tw;14 1019 [13];

BMSE(rac) 117-119 and 118-120 ; 128-130; 132-133 36;14;16

g

c

h

BESE

142-145; 149-149.5; 148-149; 150

1

015 (3,tw)

1012 (13);

010 (tw)

i

BPSE

161-162.5; 162-164

13; tw

1

BBSE

BPeSE

BCySE

BHSE

172-173

134-135

172-174

tw

19; 5

tw

13

tw

1014

1014,1073,1100

1018

176.5-177.5

1016,1114

1033 [5]

1037 [5]

1035,1089

1050 [3]

1016,1047

1021,1075

1021

j,k

BPhSE(RS) 166-167

BPhSE(SS) 120-122; 122-123

j

k

BPhSE

BMSP

BESP

BPSP

BBSP

BPeSP

BPhSP

165-170

117-118

127-130

140-143

146-148

125-129

137-140

l

1026

1021,1040,1084

a

b-d

and ^g^-^lindicate the recrystallization solvents that were used in each case.

tw, this work. The superscripts

b

c

d

e

-1

EtOH/ethyl acetate. EtOH. Acetone/ethyl acetate. The value 1018 cm is quoted for a crude product (M. p.

25-164  C). Recrystallized from the mother liquor using ethyl acetate and toluene. Benzene. Ethyl acetate.

f

g

h

1

i

j

k

l

Benzene/hexane 3:2. Chloroform and petroleum ether. CHCl /light petroleum and ethanol. THF.

3

n

of RS(O)(CH ) S(O)R [R = Me (BMSE) [16] and Pr (BPSE) and phenyl (BPhSE) [5] suggest that

2

generally the higher melting isomer is that of the meso form (vs. the rac form) (Table 2) [19].

1

2

Our attempts to crystallize the disulfoxides were unsuccessful; attempts included variation of solvent

combinations, temperatures, and sublimation methods. For example, some "crystals" of BPSP were

found not to be single crystals of X-ray quality, as found by others [20]. Svinning et al. [16] have noted

that crystals of the lower melting isomer (rac-BMSE) were “clusters of interpenetrating needles that

were easily shattered or deformed”.

An attempt to synthesize 1,2-bis(ethylsulfinyl)methane (BESM) following the procedure given in

Section 2.2.1, but using BETM (9 mL, 79 mmol), DMSO (10.44 mL, 158 mmol) and conc.

HCl(200 uL), was unsuccessful. An isolated, white powder product was purified by sublimation under

o

vacuum at 80 C, but was insoluble in most common solvents and only slightly soluble in DMSO.

Elemental analyses, NMR and mass spectrometry data were inconclusive.

3

.2. The disulfoxide complexes

.2.1. General comments

Our group initially used cis-RuCl (DMSO) and cis-RuCl (TMSO) as precursors for synthesis of

3

2

4

2

4

biologically active RuCl (sulfoxide) (nitroimidazole) complexes [21], and, in order to reduce the

2

number of possible isomers in such complexes, disulfoxides were subsequently used. This first led us to

report in 1997 syntheses of the fully characterized complexes (i.e. with X-ray structures) cis-

RuCl (BMSP) , trans-RuCl (BMSE) (complex 1), cis-RuCl (BESE) (2), and trans-RuCl (BPSE) ; the

2

Ru-blue solution formed by H -reduction of RuCl ·3H O in MeOH was used as the Ru-precursor [3]. In

2

3

2

this current paper, five cis and two trans complexes of the type RuCl (disulfoxide) (2 to 8) are isolated

2

using other Ru precursors. Of interest, the earlier synthesis of 2 gave a 55% yield [3], about 20% higher

than using K [RuCl ] as precursor (Section 2.3.2); 2 has also been synthesized using as precursors

3

6

RuCl

٠

3H O, the Ru-red solution, and trans- or cis-RuCl (DMSO) , yields being about 70, 50, and 35

3

2

4

%

, respectively [22]. Coincidentally, the same yield of 47% was found for trans-RuCl (BPSE) (4),

2 2

using either the Ru-blue solution or cis-RuCl (DMSO) .

2

4

Obvious is that reaction products depend on the ratio of disulfoxide: Ru; e.g., a 2:1 ratio with BBSE

forms a mononuclear bis(disulfoxide) complex (5), whereas with a 1:1 ratio the product is 11, a

dinuclear, bridged chloro species. Unique is the 2:1 ratio with BPhSE that forms the bridged disulfoxide

1

3

complex 13; this could result from a steric factor, although the related BCySE at the 2:1 ratio gives 7,

the mononuclear bis(disulfoxide) complex.

All the RuCl (disulfoxide) complexes contain only S-bonded disulfoxides as seen by IR data (Table

2

S1). The disulfoxide ligands in the four earlier published structures have opposite chiralities at the two

chiral S-atoms [3], whereas the trans complexes are centrosymmetric, with mutually trans S-atoms

having opposite configurations, and are non-chiral. The two cis-complexes have C symmetry with the

2

pair of mutually trans S-atoms having the same chirality. The cis-complexes are chiral, but in both cases

the crystal structures showed that the samples contain an equal number of the two enantiomers [3].

There is special interest in these complexes, because the trans Ru-disulfoxide species accumulate in

cells and bind to DNA to a greater extent than the cis-species, leading to greater in vitro biological

activity [3].

Both cis- and trans-RuCl (DMSO) were tried as precursors in sulfoxide-exchange reactions;

2

4

however, reaction of trans-RuCl (DMSO) (or RuCl 3H O) with BESE gave cis-RuCl (BESE) (2)

2

4

3

2

(

Section 2.3.2), and reaction of cis-RuCl (DMSO) with BPSE gave trans-RuCl (BPSE) (4) (Section

2 4 2 2

2

.3.4). Attempts to use photolysis to affect the isomerization of cis-RuCl (BESE) to trans-

2 2

RuCl (BESE) , as reported by Alessio et al. for the isomerization of cis-RuCl (DMSO) to trans-

2

4

RuCl (DMSO) [23], were unsuccessful. Of interest, the fully characterized, water-soluble complex

2

4

[

RuCl(BESE)(H O)] (-Cl) (9) (Section 2.4.1) with two equivalents of BESE did generate trans-

2

RuCl (BESE) (3). In attempts to synthesize mixed disulfoxide complexes, 9 was also reacted with

2

BESP; however, cis-RuCl (BESE) was obtained by recrystallization of the reaction product from

2

aqueous solution. An electrospray mass spectrum of 9 in aqueous solution showed peaks at 709 [M⁺-

+

Cl], 690 [M - Cl - H O ], and 672 [M - 2Cl], showing that the dimer does not dissociate to monomer.

2

The Calligaris group carried out a molecular mechanics investigation of three of our complexes,

and concluded that complexes 1, 2 and 4 correspond to the lowest strain diastereomers [24]. Figure 1

shows basic S-bonded structures of the cis- and trans-complexes. Further, the minimum energy structure

for a cis-isomer, e.g. 2, is the diastereomer containing meso-BESE ligands, and this requires trans S-

atoms with the same R or S chirality. The lowest energy for 1 and 4 is with mutually trans S-atoms of

opposite chirality. Analogous diastereomers have been observed in the crystal structures of both trans-

RuCl (BMSE) and trans-RuCl (BPSE) [3,24].

2

1

4

Cl

Ru

Cl

S

Cl

S

Cl

S

Ru

S

1

, 4

2

8

Figure 1. Basic structures, not showing the alkyl groups or the O-atoms attached to the S-atoms: e.g. trans-

RuCl (BMSE) (1), cis-RuCl (BESE) (2), trans-RuCl (BPSE) (4), and cis-RuCl (BESP) (8); S^S = chelating

2

disulfoxide.

The S-bonded disulfoxides are confirmed by crystallography data for all the complexes 3-8, except

. In contrast to the water-soluble, bridged chloro-complexes 9-12 (Sections 2.4, 2.5), no conductivity

6

was observed for complexes 3-8 in chlorinated solvents. As well as three Ru₂^I^Ichelating disulfoxide

II

III

complexes (9-11), with [RuCl(BESE)(H O)] (-Cl) (9) being structurally characterized, a Ru /Ru ,

2

mixed-valence complex [RuCl(BPSP)] (-Cl) (12) was isolated (Section 2.5.1). Again, all these

2

3

complexes contain only S-bonded sulfoxides.

i

Reactions of BPhSE, BHSE, B PSP, BBSP, BPeSP, BPhSP and BMSB with RuCl 3H O, using the

3

2

Section 2.3.5 procedure, gave yellow, uncharacterized products that in column chromatography showed

several bands or, in the case of BMSB, the isolated product was insoluble in common solvents.

Elemental analyses for products obtained from the major chromatography bands, and the BMSB

product, were variable from repeat reactions.

Of note, an attempt to oxidize 1,3-bis(phenylthio)propane (BPhTE) to BPhSP using air/DMSO

1

oxidation led to an oily product, which by TLC, H NMR spectroscopy and  data, appeared to be the

SO

disulfoxide. However, reaction of this oil with RuCl 3H O, using the procedure described in Section

3

2

.3.5, led to the isolation of red crystals that were submitted for X-ray analysis. The structural diagram

(

Figure S1) revealed cis-RuCl (BPhSP)(1-phenylthio-3-(phenylsulfinyl)propane), i.e. one coordinated

2

disulfoxide and one ‘half-oxidized’ dithioether! Large thermal motion prevented an accurate

determination of the structure; however, cis geometry was established. The oxidation of dithioethers

using just one-half of the required oxidant could more generally lead to a novel series of such

thioether/sulfoxi Ru complexes.

1

5

3

-

Of interest, the in situ reduction of both the RuCl 3H O and the Ru(III) precursor [RuCl ] to Ru(II)

3

2

6

products is possibly due to the disulfoxide acting as a reductant that is oxidized to the corresponding

sulfone; this might account for the relatively low yields in syntheses using either the 2:1 or 1:1

disulfoxide:Ru ratios. Higher yields might result by using increased sulfoxide concentration. The redox

process is mentioned in Section 3.2.3 and has been discussed previously [1].

3

.2.2. RuCl (disulfoxide) complexes 3 to 8

2 2

1

The H NMR spectrum (in D O) of free BESE consists of multiplets at  3.30 (CH CH ), 2.92

2

(

CH CH ), and a triplet at 1.23 (CH ), which in trans-RuCl (BESE) (3) are shifted downfield to a

3 2 3 2 2

coalesced peak at  3.70 (for the CH protons) and a multiplet at  1.45 (CH ); the spectrum does not

2

3

change over 3 weeks, and is consistent with the trans crystal structure. Complex 3 crystallizes in a

centrosymmetric space group (Figure 2), with slightly distorted octahedral geometry at the Ru with trans

angles of 180.0 º and cis angles that range from 85.43(4)-90.87(3) º (Table 3); the structural data are

similar to those of trans-RuCl (BMSE) (1) and trans-RuCl (BPSE) (4) [3]. Indeed, the key bond

2

II

lengths and angles are very similar in all the Ru -disulfoxide complexes : e.g., the S-O bond lengths for

complexes 2-5, 7 and 8, and even for the dinuclear [RuCl(BESE)(H O)] (-Cl) (9), average about 1.48

2

Å with little change (+ 0.04 Å) (see Tables 3, S2). Table 4 shows the relative configurations of the S-

atoms seen in the RuCl (disulfoxide) structures.

2

1

6

Figure 2. An ORTEP drawing of trans-RuCl (BESE) (3) with 50 % probability thermal ellipsoids

2

shown.

An attempted, new synthesis of trans-RuCl (BPSE) from cis-RuCl (DMSO) was essentially

2

4

successful, but the product, complex 4, contained an H O solvate. The NMR data in CD Cl agreed with

2

the published data for the non-solvated complex [3].

Table 3. Selected Bond Lengths (Å) and Bond Angles (º) for [RuCl(BESE)(H O)] (-Cl) H O, trans-

2

RuCl (BESE) and cis-RuCl (BESE) .

2

a

Bond or Angle [RuCl(BESE)(H O)] (-Cl) H O Trans-RuCl (BESE)

Cis-RuCl (BESE)

2 2

2

b

e

c

d

Ru-Cl

Ru-S

2.4087(10); 2.4636(10)

c

2.4217(8)-2.4486(8)^d

2.3994(11)

2.4022(8)

2.3209(9), 2.3288(9)

c

f

c

2.1985(9); 2.1961(13)

2.2712(8)-2.2738(8);

d

2

.2973(8)-2.3076(8)

Ru-O

S-O

C-S

2.138(2)^d

1.477(2), 1.489(2)

1.805(4)-1.795(3)

82.14(4)-95.01(4)

171.75(3)-177.88(7)

96.89(4), 97.86(4)

99.33(17)-103.1(17)

104.49(18)-107.45(14)

118.39(10)-120.53(13)

106.3(2)-109.5(2)

111.6(2)-113.7(3)

105.32(12)-107.14(13)

115.22 (13)

1.478(12)-1.479(2)

1.794(3)-1.809(3)

85.43(4)-90.87(3)

180.0

1.470(2)-1.479(2)

1.796(3)-1.814(3)

87.19(3)-92.08(3)

176.92(3)-178.54(3)

cis angles

trans angles

Ru-Cl-Ru

C-S-C

99.18(15)-101.33(15)

106.62(14)-108.15(15) 106.3(1)-109.3(1)

100.0(1)-102.8(1)

O-S-C

Ru-S-O

119.42(9)-119.42(10)

106.72(19)-110.7(2)

111.1(2)-112.4(2)

103.47(11)-104.83(11) 103.0(1)-104.8(1)

115.70(11)-116.75(11) 113.4(1)-117.3(1)

116.28(8)-120.43(8)

106.5(2)-111.0(2)

111.3(2)-112.0(2)

g

S-C-C

h

g

Ru-S-C

h

a

Data taken from ref. 3. Bridging. Trans to Cl. Of coordinated H O, trans to S. ^eTerminal.

b

c

d

2

f

g

h

Trans to O. Backbone. End substituents.

Table 4. The Relative Configurations of the S-atoms in Chelating Disulfoxide Complexes of Ru; S(4)

and S(3) are taken as trans to S(2) and S(1), respectively.

Complex

S(1)

S(2)

S(3)

S(4)

1

7

a

trans-RuCl (BMSE)

R

S

R

S

R

S

R

2

a,b

c

d

c

d

cis-RuCl (BESE)₂

R

S

R

S

R

2

b

trans-RuCl (BESE)₂

2

a,b

trans-RuCl (BPSE)₂

S

2

b

c

d

c

d

cis-RuCl (BBSE) EtOH

R

2

b

d

c

d

cis-RuCl (BCySE)₂

S

R

2

a,b

d

cis-RuCl (BMSP)₂

2

b

c

d

e

c

d

cis-RuCl (BESP) EtOHH O

S

2

b

c

[

RuCl(BESE)(H O)] (-Cl) H O

2

b

c

R^c

S^c

[

RuCl(BPSP)] (-Cl) 2H O2.5CH Cl

2

3

2

a

b

c

d

e

Data taken from ref. 3 Unit cell contains both isomers. Trans to Cl. Trans to S. Trans to O.

1

Cis-RuCl (BBSE) (5, Figure 3) was synthesized in 21% yield from RuCl ·3H O. The H NMR shifts

2

3

2

are downfield of those of free BBSE that was not detected in the spectrum. The crystal structure

revealed an EtOH solvate; selected bond lengths and bond angles (Table 5) are comparable to those of

cis-RuCl (BCySE)₂(Table 5), cis-RuCl (BESE) (Table 3), and cis-RuCl (BESP) and cis-

2

RuCl (BMSP) (Table S2, and ref. 3). Of note, opposite chiralities of the S(3) and S(4) atoms are found

2

on one BBSE, and the same chiralities of S(1) and S(2) atoms on the other BBSE; this is the only

complex with S(1) and S(2) having the same chirality (Table 4). The synthesis of 5 seemed plausible by

use of a mixture of meso- and rac-BBSE, but the sharp melting point (Error! Reference source not

found.) implies only one diastereomer of the ligand was present. The solvated complex is chiral with

approximately C symmetry, but the crystal structure is centrosymmetric and contains an equal number

2

of the two enantiomers. Figure 3 shows the  isomer in which both trans S-atoms have R configuration.

The unit cell shows the EtOH is H-bonded to both an O-atom and a Cl-atom; the H--O and the H--Cl

distances are 2.12 and 2.71 Å, respectively, which are 0.58 and 0.19 Å shorter than the sum of the van

der Waals radii of an O- and H-atom, and a Cl- and an H-atom, respectively [25], implying relatively

strong interactions.

Cis-RuCl (BPeSE) (6) required purification by column chromatography, and was obtained in only

2

1

9

% yield. The H NMR shifts of BPeSE are again seen downfield upon coordination. The CH signals

3

were seen as a multiplet (presumably 2 overlapping triplets), compared, for example, to two triplet

signals observed for cis-RuCl (BESE) (see below). The X-ray analysis prevented an accurate structure

2

due to excessive thermal motion the pentyl side-chains, but the cis geometry was established.

1

8

Figure 3. An ORTEP drawing of cis-RuCl (BBSE) ·EtOH (5) with 50 % probability thermal ellipsoids

2

shown; H-atoms (except for that of EtOH) are omitted for clarity.

1

The H NMR spectrum of cis-RuCl (BCySE) (7) is complicated because of the inequivalence of the

2

cyclohexyl rings oriented in the cis geometry. The complex is chiral, has approximate C symmetry with

2

the pair of mutually trans S-atoms having the same S-chirality, and crystallizes in a centrosymmetric

space group that contains equal numbers of the two enantiomers; Figure 6 depicts the  isomer in which

the trans S-atoms both have S configuration. The molecule has a slightly distorted octahedral geometry

at the Ru with trans angles ranging from 176.38(5) to 178.01(5) º and cis angles from 86.27(5) to

9

6.50(5) º (Table 5). Bond lengths and angles are comparable to those of cis-RuCl (BBSE) EtOH

2

(

Table 5and cis-RuCl (BESE) (Table 3). Each disulfoxide has opposite chiralities at the two chiral S-

2 2

atoms (Table 4).

1

9

As with complex 6, column purification was needed to give a 36% yield of cis-RuCl (BESP) (8)

2

1

Again, downfield H NMR shifts of BESP are generally seen on its coordination, although the δ 2.45

multiplet of the free ligand becomes two multiplets at δ 2.75 and 2.10. The key bond lengths and angles

(

Table 6) are close to those of cis-RuCl (BMSP) [3] and the other cis-RuCl (disulfoxide) complexes.

2 2 2 2

The complex crystallizes in a centrosymmetric space group and contains equal numbers of the two

isomers; Figure 4 depicts the  isomer in which the trans S-atoms both have the R-configuration; the

unit cell contains a water molecule H-bonded to an O-atom of a disulfoxide and to the EtOH solvate

(Figure 5). The average H--O distance is 1.89 Å, which is 0.81 Å shorter than the sum of the van der

Waals radii of an H- and an O-atom (2.70 Å), implying strong H-bond interactions between the water

molecule, and the complex and the EtOH [25].

Table 5. Selected Bond Lengths (Å) and Bond Angles (º) of cis-RuCl (BBSE) EtOH and cis-

2

RuCl (BCySE) .

2

Bond or Angle cis-RuCl (BBSE) EtOH

cis-RuCl (BCySE)

2.4217(9), 2.4398(9)

2

a

Ru-Cl

Ru-S

2.4101(11), 2.4294(9)

a

2.3059(11), 2.3059(11); 2.2658(10),

2.3428(9), 2.3500(9); 2.3008(9),

b

2

.2918(10)

2.3008(19)

a

b

a

b

S-O

1.479(3), 1.482(3); 1.468(3), 1.481(3)

1.795(4)-1.833(5)

1.451(3), 1.462(3); 1.483(2), 1.489(3)

1.797(3)-1.856(5)

C-S

cis angles

trans angles

Ru-S-O

O-S-C

85.59(4)-96.21(4)

86.13(3)-96.78(3)

172.98(3)-177.39(3)

116.97(11)-118.96(13)

105.41(18)-109.1(2)

101.6(2)-102.9(2)

107.2(3)-112.6(3)

111.3(3)-113.9(3)

176.34(13)-178.05(3)

117.6(11)-119.69(13)

106.73(15)-108.5()

98.93(17)-104.83(17)

107.2(3)-110.2(2)

106.0(2)-113.8(5)

101.75(12)-104.44(12)

115.64(2)-118.37(11)

C-S-C

S-C-C

c

d

c

Ru-S-C

102.77(17)-104.59(15)

114.16(14)-119.88(14)

d

a

Trans to S. ^bTrans to Cl. Bonds involving backbone carbons. The C-atom of an alkyl substituent.

c

d

2

0

Figure 4. An ORTEP drawing of cis-RuCl (BESP) ·EtOH·H O with 50 % probability thermal

2

ellipsoids shown; H-atoms are omitted for clarity.

2

1



H O

2

EtOH

Figure 5. The unit cell of cis-RuCl (BESP) ·EtOH·H O (8) showing the EtOH and H O solvate

2

molecules.

2

Figure 6. An ORTEP drawing of cis-RuCl (BCySE) (7) with 50 % probability thermal ellipsoids

2

shown; H-atoms are omitted for clarity.

Table 6. Selected Bond Lengths (Å) and Bond Angles (º) of cis-RuCl (BESP) ·EtOH·H O and cis-

2

RuCl (BMSP) .

2

a

Bond or Angle cis-RuCl (BESP) ·EtOH·H O

cis-RuCl (BMSP)

2

b

Ru-Cl

Ru-S

2.4211(10), 2.4299(11)

2.4354(7), 2.4395(7)

2.3518(7), 2.3569(7); 2.2682(6),

b

2.3307(11), 2.3549(10); 2.2751(10),

c

2

.2892(11)

2.2710(6)

b

c

b

c

S-O

C-S

1.487(3), 1.491(3); 1.477(2), 1.491(3)

1.791(4)-1.820(3)

1.473(2), 1.480(2); 1.476(2), 1.480(2)

1.773(3)-1.801(3)

83.42(2)-97.55(2)

174.21(2)-178.42(2)

113.91(8)-116.51(9

104.9(1)-107.1(1)

98.9(2)-100.6(1)

cis angles

trans angles

Ru-S-O

C-S-O

84.93(4)-97.66(4)

171.62(4)-175.51(3)

113.63(12)-118.45(12)

105.86(17)-107.69(18)

98.58(19)-102.1(2)

112.3(3)-116.4(3)

111.8(3)-113.0(3)

C-S-C

S-C-C

d

114.4(2)-115.6(2)

e

S-C-C

C-C-C

Ru-S-C

112.0(3)-117.8(3)

110.03(12)-115.69(14)

112.08(13)-115.49(14)

113.1(3), 113.4(2)

115.3(1)-115.80(9)

111.2(1)-113.6(1)

d

e

a

Data taken from ref. 3 Trans to S. ^cTrans to Cl. ^dBonds involving backbone carbons. The C-atom

b

e

of an alkyl substituent.

2

3

II

3

.2.3. Dinuclear Ru -chelating disulfoxide complexes

2

The syntheses of cis-RuCl (BESE) involved reaction of two equivalents of BESE with one of a Ru

2

precursor (Section 2.3.2). However, on use of just one equivalent of the disulfoxide with RuCl

٠

3H O,

3

2

the water-soluble, structurally characterized, dinuclear Ru₂^I^Icomplex [RuCl(BESE)(H O)] (-Cl) (9)

2

(Section 2.4.1) was obtained, and the BPSE and BBSE analogues (10 and 11), also water-soluble, were

made similarly (Sections 2.4.2, 2.4.3). As noted (Section 3.2.1), and of importance, reaction of 9 with

two equivalents of BESE then led to isolation of trans-RuCl (BESE) (3) (Section 2.3.3). The

2

1

disulfoxides in 9-11 are all S-bonded, this being consistent with H NMR spectra (in D O) that show

2

II

III

appropriate downfield shifts from the resonances of the free ligand [27]. A mixed-valence Ru /Ru

III

complex [RuCl(BPSP)] (-Cl) (12) (Section 2.5), and a Ru complex [RuCl (BPhSE)] (μ-BPhSE)

2

3

2

3

2

(13) (Section 2.6) were also isolated, and these complexes also contained only S-bonded sulfoxides.

-4

The "equilibrium" conductivities for 9-11 in water (~ 10 M,  358, 282 and 497, respectively),

M

correspond to those of a 2:1-3:1, 2:1 and 3:1 electrolyte, respectively, when compared to those of salts

26]. Addition of aq. NaOH to 9 showed that two protons/molecule are titrated (Table S3). Further, the

[

-3

measured equivalent conductance of 10 M HCl, ~ 430 (cf. literature value of ~ 420 at 25 C [28] was

-3

reduced to ~ 350 on addition of 10 M aq. solution of cis-RuCl (BESE) whose molar conductance is ~

2

+

-

3

3.9 [3]). The conductivity data are consistent with loss of 2 equiv. of both H and Cl per molecule of 9,

1

and thus the the H NMR data (in D O) presumably refer to such a species. Addition of 2 equivalents of

2

1

AgNO to a solution of 9 formed an immediate precipitate of AgCl, but the H NMR spectrum of the

3

filtrate was the same as that of the spectrum of 9; addition of a further equivalent of AgNO to the

3

1

filtrate gave no precipitate, and the H NMR was unchanged. Of note, the C-analyses of 10 and 11 differ

from the calculated values by ~0.4, somewhat outside acceptable values; reactivity with moisture is the

most likely reason for this.

The structure of 9 is shown in Figure 7, and selected bond lengths and angles are given in Table 3,

with those of cis- and trans-RuCl (BESE) . The asymmetric unit consists of two independent half-

2

molecules and a water molecule (Figure 8), the H(33)--O(4) and H(34)--Cl(2) distances, 1.81 and

2

8

.28 Å, respectively, indicating strong H-bond interactions. The cis and trans-angles at the Ru are from

2.14 to 95.01º and 171.75 to 177.88º, respectively. The Ru-Cl-Ru bridging angles are 96.89 and 97.86º,

2

4

the Ru-atoms being further apart than the 70.53 of an ideal cofacial bioctahedron [29]; no Ru-Ru

interaction was detected out to 3.90 Å. The usual range for a Ru-Ru bond with bridging ligands is

typically ~ 2.28 to 3.04 Å [30].

Figure 7. An ORTEP drawing of [RuCl(BESE)(H O)] (-Cl) (9) showing the H O solvate.

2

The BPSE and BBSE complexes presumably have the corresponding dinuclear, dichloro-bridged

structures. All three, water-soluble, complexes (9-11) were tested in vitro for cytotoxicity, accumulation

and DNA-binding properties in Chinese hamster ovary cells; findings with these and other Ru-

disulfoxide species [4] will be reported elsewhere.

From the general synthetic procedure for the RuCl (disulfoxide) complexes (Section 2.3.5.), but

2

using BPSP, a 15 % yield of the unexpected dinuclear, water-soluble, mixed-valence complex

RuCl(BPSP)] (-Cl) (12) was obtained. The structure of a crystal, obtained from a saturated solution

[

2

3

of CH Cl (Figure 8) confirms the S-bonded disulfoxides, also evident from the  data (Table S1), and

2

SO

also reveals 2H O and 2CH Cl solvates per molecule. The complex crystallizes in an acentric space

2

group containing a glide plane and thus the crystal structure contains enantiomeric pairs. Figure 8

depicts one of the enantiomers, whereas Figure 9 shows the four H-bonded H O molecules that

2

‘connect’ the two asymmetric units. The chiralities at the S-atoms on each of the BPSP ligands are R and

S, respectively (Table 4). Selected bond lengths and angles for the two asymmetric units are given in

Tables 7 and 8, respectively; the two Ru-atoms are indistinguishable, consistent with a delocalized

2

5

II

III

Ru /Ru system. The bond lengths are in fact comparable to those found in [RuCl(BESE)(H O)] (-

2

Cl) showing the H O solvate., for e.g., Ru-Cl is 2.466-2.482 Å (bridging, trans to S) and Ru-S is 2.198-

2

7

.225 Å (Table 7). In more detail, the geometry about each Ru is irregular octahedral with cis angles of

9.36-97.51º and trans angles of 168.64-174.64º (Table 8). The μ-Cl trans to terminal chlorides has a

shorter Ru-Cl distance 2.386-2.408 Å) than the μ-Cl ligands trans to sulfur (2.466-2.482. (Table 7). This

implies a weaker trans influence of the chloro ligands that produces a wider Ru-Cl(1)-Ru angle (84.62

and 85.02º) compared to the other two Ru-Cl-Ru (81.24-82.60º). The range of the bridging angles and

the Ru-Ru distance (3.230 and 3.232 Å) is outside those observed for a Ru-Ru bonded system [29].

The distances between the water H-atom and the disulfoxide O-atoms distances are 1.61-1.76 Å;

these

are much shorter than the sum of the van der Waals radii of the atoms (2.70 Å) [25], showing strong H-

bonds interaction between the two asymmetric units. The same approach for degree of H-bonding of the

CH Cl to the O-atoms reveals very weak interactions (2.77-2.93 compared to 2.90 Å) [25]. Of interest,

2

a

n+

reported structure has shown parallel layers of [Cu(BPSP) (ClO )] cations that are intercalated by

2

4 n

-

n[ClO ] anions with the O-atom of the BPSP acting as a bridging link between the Cu atoms [31].

4

2

6

Figure 8. An ORTEP drawing of one unit of [RuCl(BPSP)] (-Cl) (12) with 50 % probability thermal

2

3

ellipsoids shown; H-atoms are omitted for clarity.

Figure 9. A diagram of [RuCl(BPSP)] (-Cl) (12) showing short H-bonds connecting two asymmetric

2

3

units via 4 H O molecules (the CH Cl atoms are not shown).

2

1

The broad H NMR shifts, seen for 12 in D O, with the exception of the Me multiplet at 0.90, are

2

1

again downfield of the free ligand shifts. The H spectrum in CDCl consists of two broad peaks at 

3

II

III

2

0

.18 and 1.10 are consistent with delocalized Ru /Ru centres. The solution  value in CDCl ,1.7 

eff

3

1

.1 B.M. is consistent with one unpaired electron per dimer molecule. The crystallographic and H NMR

data suggest that complex 12 is best formulated as a valence-delocalized class III system [32].

The complex exhibited no conductivity in CHCl , but  in H O (per mole of dimer) increased to a

3

M

2

steady value of 234 at 20 min, the value of a 2:1 electrolyte (see Section 3.2.3); the chemical behaviour

in aqueous solution has been studied further [4], and details will be published together those of the other

water-soluble complexes 9-11 [33].

2

7

The low synthetic yield of 12 likely results from redox chemistry, this being indicated by a distinctive

dithioether odour detected during the workup of the synthesis. This could be formed by oxidation of Ru^I^I

III

(

formed by EtOH reduction of RuCl 3H O) that could then be re-oxidized to Ru by the disulfoxide

3

2

that would be reduced to the dithioether [1].

Table 7. Selected Bond Lengths for the Two

Asymmetric Units of [RuCl(BPSP)] (-Cl)

2

3

Bond

Length (Å)

Ru-Cl^a2.386(2)-2.408(2);^b

c

2

.466(2)-2.482(2)

Ru-Cl^d2.381(2)-2.391(15)

Ru-S

S-O

C-S

2.198(2)-2.225(3)

1.475(7)-1.497(7)

1.790(10)-1.811(10)

a

b

c

d

Bridging. Trans to Cl. Trans to S. Terminal.

Table 8. Selected Bond Angles for the Two Asymmetric Units of [RuCl(BPSP)] (-Cl) .

2

3

Bond angle

Angle (º)

Angle

Angle (º)

cis angles

trans angles 168.64(9)-174.64(9)

Ru-Cl-Ru

C-S-C

O-S-C

79.36(8)-97.51(8)

Ru-S-O

117.4(3)-119.8(3)

109.5(7)-113.3(8)

110.9(7)-117.3(7)

111.2(3)-112.3(4)

111.0(3)-115.0(3)

a

S-C-C

81.24(7)-82.60(7) 84.62(7) and 85.02(7)^dS-C-C

c

b

a

b

99.7(5)-101.6(5)

102.2(5)-106.8(5)

Ru-S-C

a

b

c

d

Backbone. End substituents. Trans to sulfur. Trans to chloride.

3

.2.4 A Dinuclear Ru^I^I^I₂complex with a chelated and a bridging disulfoxide

The compound [RuCl (BPhSE)] (BPhSE) was isolated with one or two H O solvate molecules,

3

2

complexes 13a and 13b, respectively, depending on the Ru precursor: RuCl

٠

3H O and K [RuCl ]

3

2

3

6

1

formed 13a, whereas the blue and red Ru solutions gave 13b. The H-NMR data show paramagnetic

species, and repeat elemental analyses support the formulation with one or two water molecules. The IR

-1

stretches 1070, 1082, 1105, and 1116 cm reveal S-bound sulfoxide when compared with the values for

-1

free BPhSE (1035, 1089 cm ), and no bands are seen in the region of O-bound sulfoxide. The mass

+

spectrum shows peaks at 1142 [M -3 Cl], and 972 [M -BPhSE]. The complexes were non-conducting

2

8

-1

2

-1

in CH Cl (0.6  cm mol ) [26]; dissolving them in DMSO immediately formed trans-RuCl (DMSO)

2

4

1

as shown by H-NMR data. There is no direct evidence for the bridging disulfoxide, but the formulation

shown is the most obvious. Such complexes with bridging S-disulfoxide or O-disulfoxide complexes are

known, e.g. with Pt [34] and Cu [31], respectively, and we have reported on [RuCl (p-cymene)] (μ-S-

2

disulfoxide) species with BESE, BESP, and [RuCl(p-cymene)(BESE)]PF [35] but, to the best of our

6

knowledge, 13a/b are the first Ru(III) complexes with a bridging disulfoxide.

4

. Conclusions

The oxidations of recently reported dithioethers RS(CH ) SR, where n = 2 or 3 and R is an alkyl or

2

n

aryl chain [1], to the corresponding disulfoxides R-S(O)-CH ) -(O)S-R were successful. Their reactions

2

n

with various Ru precursors provided a surprisingly wide range of S-bonded sulfinyl complexes of the

II

types

cis

and

trans-Ru Cl (disulfoxide)

[Ru Cl (disulfoxide)(H O)] (μ-Cl) ,

and

2

2,

2

Ru₂^I^I^/^I^I^ICl(disulfoxide)] (μ-Cl) that were well characterized, including X-ray data. A further Ru

III

[

2

3

2

complex,

probably

RuCl (BPhSE)] (μ-BPhSE)

with

the

bridging

disulfoxide

1,2

3

2

bis(phenylsulfinyl)ethane, was also synthesized. Some of the complexes, especially the water-soluble

species, have potential for biological properties, such as cell accumulation and toxicity, and DNA

binding [3]. The key synthetic work in our recent paper [1] and in this current paper is now complete,

and biological findings on the new disulfoxide species are now being organized for publication.

Acknowledgements

We thank the Natural Sciences and Engineering Research Council of Canada (NSERC, Grant CRDP

J 234014) and the Medical Research Council of Canada for financial support, and Colonial Metals Inc.

for the RuCl

٠

3H O.

3

2

Appendix A. Supplementary data

Supplementary material contains Table S1-S3, and Fig. S1. Full experimental parameters and details

of the structures are given in CIF format in the Supplementary Information; CCDC numbers 1946430-

1

946435 contain the supplementary crystallographic data for complexes 3, 12, 8, 5 7 and 9, respectively;

these data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

2

9

Article Doi

Synthesis and characterization of new disulfoxides, and their Ru complexes

DOI: 10.1016/j.ica.2019.119217

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Article abstract of DOI:10.1016/j.ica.2019.119217

Full text of DOI:10.1016/j.ica.2019.119217

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